Zoster vaccine safety

In a follow-up to the December 2012 GACVS meeting at which a general summary of varicella vaccine safety was presented, experts from the US Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC) presented systematic post-licensure safety reviews of the zoster vaccine (Zostavax®) and safety of varicella vaccine in immunocompromised populations. The FDA completed a 7-year safety update of Zostavax® by summarizing key post-licensure observational studies conducted by CDC and Merck, a literature review from the date of licensure (May 2006) through February 2013, and analysis of reports from the Vaccine Adverse Event Reporting System (VAERS) from May 2006 through February 2013. The CDC Vaccine Safety Datalink study on Zostavax®, together with 3 post-licensure studies conducted by Merck as FDA regulatory commitments, included a total of >190 000 vaccinated study subjects. No new safety signals were identified in these studies. More than 12 000 reports were submitted globally for Zostavax® to VAERS from May 2006 through February 2013, of which 1057 were considered serious. The 3 most frequent terms for serious adverse events were herpes zoster, pain, and rash. FDA data mining using disproportionate analysis revealed adverse events predominantly associated with vaccine failure (i.e. herpes zoster despite vaccination), as well as accidental exposure and inappropriate vaccine administration (i.e. use of Zostavax® in subjects younger than the FDA approved age of ≥50 years). In summary, although safety data on the subpopulation of individuals aged ≥80 remains limited, no new safety risks have been identified or confirmed since initial licensure.

Safety of varicella vaccine in immunocompromised populations

Because diseases caused by wild type VZV are more severe and fatal in persons with defects in cell-mediated immunity, varicella vaccine has been studied for safety and efficacy in select immunocompromised populations. Studies of the safety and effectiveness of varicella vaccines were conducted in children with cancer, HIV, and post-organ transplant. All but one of the studies was conducted in developed countries. Compared to healthy children, varicella vaccine is associated with a higher risk of adverse reactions, some severe, in selected subpopulations of children with deficiencies in cell-mediated immunity. Varicella vaccine is contraindicated or should be used with caution, under strict protocol, in persons with leukaemia. Two doses of varicella vaccine are effective and safe in preventing varicella in children with HIV with CD4 T-cell count ≥15%. Case reports were identified describing other immunocompromised children primarily due to natural killer T-cell deficiency discovered after vaccination. In countries with routine childhood varicella vaccination programmes, children are likely to be vaccinated without knowledge of their immune deficiency states. The size of this group will depend largely on the prevalence of undetected and untreated HIV infection. This fact is an important consideration in introducing varicella vaccination, but should be balanced against the benefits of reducing more severe wild-type varicella disease in this subpopulation.

Full report of GACVS meeting of 12-13 June 2013, published in the WHO Weekly Epidemiological Record on 19 July 2013

A systematic post-licensure review of the varicella vaccine Varivax® (Merck) safety in the United States of America (USA) was presented in preparation for an update of the WHO position paper on varicella vaccines.³ A summary of the 2011 US Institute of Medicine (IOM) report,⁴ a literature review from December 2010 to October 2012, and review of key post-licensure observational studies from the US Centers for Disease Control and Prevention and Merck were included. The focus of the review was to update the safety profile of the varicella vaccine, especially for events considered significant. The IOM committee addressed 15 potential adverse events by a comprehensive review of the literature from 1950 to December 2010. Five events were assessed as having convincing evidence in support of a causal relationship with the vaccine: disseminated varicella infection (widespread chickenpox rash shortly after vaccination); disseminated varicella infection with subsequent infection resulting in pneumonia, meningitis or hepatitis; vaccine strain viral reactivation (appearance of chickenpox rash months to years after vaccination); vaccine strain viral reactivation with subsequent infection resulting in meningitis or encephalitis; and anaphylaxis. While the risks for these adverse events were not quantified in the IOM review, GACVS reviewed evidence from case series and other studies that demonstrated them to be rare events. Ten other adverse events were assessed to have insufficient evidence to support causality: encephalopathy, seizure, cerebellar ataxia, acute disseminated encephalomyelopathy, transverse myelitis, GBS, small fibre neuropathy, new onset arthropathy, stroke, and thrombocytopenia.

A review of more recent post-licensure safety studies of the combination measles, mumps, rubella (MMR) and varicella vaccine, which contains the same Oka strain as Varivax® (ProQuad®), identified a new risk of febrile seizures after vaccination among children aged 12–23 months, compared with children receiving separate MMR and varicella vaccination. In addition, Merck’s pregnancy registry for Varivax® revealed no cases of congenital varicella syndrome during 16 years of vaccine use and the data do not support a signal of an increased risk of spontaneous abortion or birth defects. Finally, a comprehensive literature review from 2010 to 2012 revealed no additional safety concerns.

GACVS raised several questions not covered by this review. These included: (1) whether varicella vaccination increases the risk of shifting varicella disease to older age groups, where disease is generally more serious, and whether this potential risk depends on the number of vaccine doses administered (i.e. would a single dose lead to greater risk than 2 doses and would additional booster doses be required?); (2) whether risks from currently available varicella vaccines remain similar to those described earlier; and (3) what the risk–benefit ratio of varicella vaccine use would be in low and middle income countries (LMICs) with a high proportion of undetected immunocompromised people, especially children with HIV, cancer and other immunodeficiencies. GACVS recommended that additional data are needed to determine the full safety profile of varicella vaccine if it is to be deployed in LMICs. GACVS recommended conducting surveillance for varicella disease to assess the effectiveness, as well as enhanced vaccine adverse event monitoring if varicella vaccine is introduced in LMICs.

Noting that substantial new safety evidence has accumulated since the last WHO report in 1998, GACVS concluded that additional data should be gathered and reviewed to complete the full benefit–risk assessment of varicella vaccine globally.

³See No. 32, 1998, pp. 241–248.

⁴ Stratton K et al., eds. Adverse events of vaccines: evidence and causality. Washington, DC, Institute of Medicine of the National Academies. August 2011.

Full report of GACVS meeting of 5-6 December 2012, published in the WHO Weekly Epidemiological Record on 8 February 2013